Substituted 5-halo-3-phenylsalicylanilides

ABSTRACT

COMPOUNDS CHARACTERIZED BY A 5-HALO-3-PHENYLSALICYLANILIDO NUCLEUS, THE ANLIIDO GROUP OF WHICH HAVING SUBSTITUENTS OF THE GROUP NITRO, CYANO AND TRIFLUOROMETHYL. THESES COMPOUNDS ARE USEFUL AS GASTROPODICIDES.

3,639,475 SUBSTITUTED 5-HALO-3-PHENYLSALICYL- ANILIDES Jack D. Early,Bethesda, and John P. Chupp, Kirkwood, Md., assignors to MonsantoCompany, St. Louis, M0. N Drawing. Application Aug. 8, 1967, Ser. No.659,040,

now Patent No. 3,525,766, which is a division of application Ser. No.495,678, Oct. 13, 1965, now Patent No. 3,382,145. Divided and thisapplicah'on Nov. 10, 1969, Ser. No. 871,311

Int. Cl. C07c 103/30 US. Cl. 260-559 S 3 Claims ABSTRACT OF THEDISCLOSURE Compounds characterized by a -halo-3-phenylsalicylanilidonucleus, the anilido group of which having substituents of the groupnitro, cyano and trifluoromethyl. These compounds are useful asgastropodicides.

This application is a division of copending application Ser. No.659,040, filed Aug. 8, 1967, now US. Pat. 3,525,- 766, which latterapplication is a division of copending application Ser. No. 495,678,filed Oct. 13, 1965, now US. 3,382,145.

This invention relates to substituted 5-halo-3-phenylsalicylanilides ofthe structural formula wherein A is halogen of atomic weight in therange of 35 to 80 (that is chloro or bromo, but preferably chloro);wherein B is hydrogen or, and preferably, halogen of atomic weight inthe range of 35 to 80 (that is chloro or bromo, but preferably chloro);and wherein R is mononitrophenyl or mono-cyanophenyl ormono-trifluoromethylphenyl, but preferably mono-nitrophenyl, whichsubstituted phenyl groupings can be further substituted withsubstituents of the group methyl, halogen of atomic weight in the rangeof 18 to 80 (that is fluoro, chloro or bromo, but preferably chloro), ora single unlike member of the group nitro, cyano and trifluoromethyl. Asillustrative I of such are patente ,Feb. 1, 1972 one of D and aforesaidB is halogen of their respective aforedescribed halogen significancesfor same;

wherein G is methyl or, and preferably, halogen of atomic weight in therange of 18 to (that is fluoro, chloro or bromo, but preferably chloro);wherein J is trifluoromethyl or, and preferably, nitro; and but when Iis trifluoromethyl then G is halogen of atomic weight in the range of 18to 80 (that is fluoro, chloro or bromo, but preferably chloro); and

wherein K is halogen of atomic weight in the range of 18 to 80 (that isfluoro, chloro or bromo, but preferably chloro) or, and preferably,trifluoromethyl.

The compounds of this invention are prepared by reacting substantiallyone mole of a substituted 3-phenylsalicyclic acid of the structuralformula v phenylsalicylanilides so obtained are solids generally meltingabove C. and are insoluble in water.

As illustrative of the preparation of the compounds of this invention isthe following:

EXAMPLE I To a suitable reaction vessel equipped with an agitator,thermometer'and reflux condenser is charged 11.3 parts by weight of5-chloro-3-(4-chlorophenyl)salicylic acid and 111 parts by weight ofchlorobenzene. The so charged mass is heated with agitation to 70 C. andthereto is added 4.75 parts by weight of 4-cyanoani1ine followed by 2.6parts by weight of phosphorus trichloride in 22 parts by weight ofchlorobenzene. The mass is then refluxed for about 5.5 hours, thencooled to about 70 C.

whereupon and with agitation about 50 parts by weight ofwater and about50 parts by weight of 20 percent hydrodrochloric acid is added. The massis permitted to stand for about 15 minutes. The organic layer isseparated and washed first with water and then with dilute aqueoussodium bicarbonate and finally with water. The so-washed organic mass isthen stripped of volatiles under vacuum. The residue is thenrecrystallized from a dioxane-water mixture to give4'-cyano-5-chloro-3-(4- chlorophenyl)salicylanilide, M.P. 283-286 C.

EXAMPLE II Employing the procedure of Example I but replacing4-cyanoaniline with an equimolecular amount of 2-chloro- 4-cyanoanilinethere is obtained 4'-cyano-2',5-dichloro-3-(4-chlorophenyl)salicylanilide, M.P. 257-259 C.

EXAMPLE III Employing the procedure of Example I but replacing4-cyanoaniline with an equimolecular amount of3-trifluoromethyl-4-nitroaniline and recrystallizing the residue from anethanol-water mixture there is obtained 3'-trifluoromethyl 4'nitro-5-chloro-3-(4-chlorophenyl) salicylanilide, M.P. 175-176" C.

EXAMPLE IV Employing the procedure of Example I but replacing4-cyanoaniline with an equimolecular amount of 2-chloro- 4-nitroanilineand recrystallizing the residue from methylcyclohexane there is obtained4-nitro-2',5-dich1oro-3-(4- chlorophenyl)salicylanilide, M.P. 208-210 C.

EXAMPLE V Employing the procedure of Example I but replacing4-cyanoaniline and 5-chloro-3-(4-chlorophenyl)salicylic acid,respectively, with equimolecular amounts of 4-nitroaniline andS-chloro-3-phenylsalicylic acid there is obtained4'-nitro-5-chloro-3-phenylsalicylanilide, M.P. 216 219 C.

EXAMPLE VI Employing the procedure of Example I but replacing4-cyanoaniline with an equimolecular amount of 2-ch1oro- S-nitroanilinethere is obtained 5'-nitro-2,5-dichloro-3-(4-chlorophenyl)salicylanilide, M.P. 2122l4 C.

EXAMPLE VII Employing the procedure of Example I but replacing4-cyanoani1ine and 5-chloro-3-(4-chloropheny1)salicylic acid,respectively, with equimolecular amounts of 2- chloro-4-nitroaniline and5-chloro-3-phenylsalicylic acid there is obtained4'-nitro-2',5-dichloro-3-phenylsalicylanilide, M.P. 192-193 C.

In a similar manner to that aforedescribed the following substituted5-halo-3-phenylsalicylanilides of this invention are obtained from theappropriate substituted aniline and the appropriate5-halo-3-phenylsalicylic acid;

salicylanilide, 4-nitro-2',5-dichloro-3-(4-bromophenyl)salicylanilide,

M.P. 233-235 C. 5'-nitro-2',5-dichloro-3-phenylsalicylanilide, M.P.

180183 C., 5'-nitro-2-methyl-5-chloro-3-phenylsalicylanilide, M.P.

183-185 C., 5-nitro-2'-fluoro-5-chloro-3-phenylsa1icylanilide,5'-nitro-2'-methyl-5-chloro-3-(4-chlorophenyl) salicylanilide, M.P.230-231 C. 5'-nitro-2'-fluoro-5-chloro-3-(4-chlorophenyl)salicylanilide, '-nitro-2',5-dibromo-3-(4-chloropheny1)salicylanilide,5'-trifiuoromethyl-2',5-dichloro-3-pheny1salicylanilide,5'-trifluoromethyl-2'-fluoro-5-chloro-3- phenylsalicylanilide,5'-trifluoromethyl-2',5-dichloro-3Q(4-chlorophenyl)- salicylanilide,M.P. 177179 C., 5'-trifluoromethyl- '-fluoro-5-chloro-3-(4chlorophenyl)salicylanilide, M.P. 140l4l C.4'-nitro-3',5-dichloro-3-phenylsalicylanilide, M.P.

182-185 C., 4'-nitro-3',5-dibromo-3-phenylsalicy1anilide,4'-nitro-3,5-dichloro-3-(4-chlorophenyl) I salicylanilide,4-nitro-3'-fluoro-5-chloro-3-(4-chlorophenyl) salicylanilide,4-nitro-3'-trifluoromethyl-5-chloro-3-phenylsalicylanilide,

M.P. 147-149 C. 4'-m'tro-3'-trifluoromethyl-5-bromo-3-phenylsalicylanilide,4'-nitro-3'-trifluoromethyl-5-bromo-3-(4-chlorophenyl) salicylanilide,-nitro-3'-trifluoromethy1-5-chloro-3-(4bromophenyl) salicylanilide.

In the process of this invention the methods by which the compounds ofthis invention are isolated will vary slightly with the reactantsemployed and the product produced. Further purification by selectivesolvent extraction or by absorptive agents such as activated carbon orclays can precede the removal of the inert organic liquid (or solvent)when the latter is employed in the reaction system. Additionally aninert organic solvent can be added to the reaction product along withabsorptive agents for purification purposes. However, the crude reactionproduct is generally satisfactory for gastroprodicidal purposes withoutpurification.

The compounds of this invention are particularly useful in destroyinggastropods, that is the class of animal life Gastropoda within thephylum Mollusca, which cause considerable agricultural and horticulturaldamage, and particularly the snails of this class of animal life whichare the necessary intermediate host or vector in the life cycle ofvarious common parasites, as for example the trematodes or flukes whichare parasitic in man and animals causing schistomiasic and likediseases.

As illustrative of the gastropodicidal properties of the compounds ofthis invention as compared to analogues and/or position isomers thereof,which respectively are prepared by the same process as that of thecompounds of this invention employing the appropriate substitutedaniline and the appropriate substituted salicylic acid, is thefollowing:

1 Evaluation I Three snails (Planobarius corneas, which is the speciesof snail host of the cyclocoelid Tracheophilus sisowi, the blood flukeBilharziella polonica and several other trematodes) of 6 to 8 weeks ofage are placed in a 200 x 32 mm. glass tube (two replicates each of saidthree snails) and thereto is added the compound to be evaluated in theform of an aqueous dispersion thereof having a concentration of 0.1 partper million, that is p.p.m. (This dispersion is prepared by dissolvingand/or dispersing suflicient of the particular compound in ml. ofacetone to make a one percent by weight solution or mixture thereof andthen 'adding sufficient water to give dispersions of the followingtabulated concentration.) The percent kill (that is the average of tworeplicates of said three snails) at the end of 24 hours at roomtemperature for each of the following itemized compounds at a 0.1 partper million concentration was found to be as follows:

i i Percent No. Compound (melting point, 0.) kill 1 14-eyano-2,5-dichloro-3-phenylsalicylanilide 100 24-cyan0-2-ch1oro-5-bromo-3-pheny1sa1icylanilide 100 3---4-cyano-5chloro-3-(4-ch1orophenyl) salicy1ani1ide. 100 4,"4'-cyano-2,5-dichloro-&(4cholopheny1) salicylanilide 100 54'-nitro-5-chloro-3 phenylsalicylanilide 100 64-nitro-2,5-dichloro-B-phenylsalicylanilide 100 7--.4'-nitro-2'-chloro-5-bromo-3-phenylsalicylanilide 100 84'-nitro-2',5-dich101'0-3-(4-chlorophenyl) salicylanilide- 100 94-nitro-2 5-dichloro-3-(4-bromophenyl)salicylanilide- 100 4-nitro-2,E-dichlorosalicylanilide (233) 42 1142gro-2',5-dichloro-Ii-methylsalicylanilide (344- 22 12- 4-nit1 o-2,3dichlororosalicylanilide 20a20e) o 13-.4-nitro-2,3,5-trichlorosalicylanilide (229230) 0 14.-4-cyano5-chloro-3-phenylsalicylanilide (264) 0 15-.3-nitro-5-chloro-3-phenylsalicylanilide (198-201). 0 162'-nitro-4-trifiuoromethyl-5-chloro-3- (4-chlorophenyl 0 salicylanilide(178-179). 17 2-trifluor0methyl-4,5-dichloro-3-(4-chlorophenyl) 0 Isalicylanilide(165168). 18 2-trifluoromethyl -4- fluoro -5- chloro -3-(4-eh1oro- 0 phenyDsalicylanilide (158-160). '19 2,21,5-t2rigl)1loro-3-(4-chloropheny1) salicylanilide 0 20 4-thi0cyario-5-chloro-3-(4-chlorophenyl) salicylani- 0 lide (255-257). 215-nitro-2-methyl-5-chloro-3-phenylsalicylanilide 705-nitro2,5-dichlore-3-(4-chlorophenyl)salicylanihde. 100 235-trifluoromethyl-2,5-dichloro-3-(4-chlorophenyl) 70 salicylanilide. 245-trifluoromethyl -2- fluoro-5 -chloro-3 (4-chloro 100phenyDsalicylanilide. 25 5-nitro-2,fi-dichlorosalicylanilide (255-256) 026 5-nitro-2-methyl-3,fi-dichlorosalicylanilide (200).-." 0 272',5,5-trichloro-3-(4-chlorophenyl) salicylanilide (214- 0 21 284-nitro-B,5-diehloro-3-phenylsalicylanilide 100 294r111i3ro-3-trifluoromethyl-5-chloro-3-phenylsalicylan1- 100 e. 304-nitro-3-triflu0romethy1-5-ohl0r0-3-(4-ch10rophenyl- 100salicylanilide. 31 4-nitro-3-trifluoromethy1-5-chlorosalicylanilide(197- 0 19 32 3-. trifiuoromethyl-t fiuoro-5- chloro-3-(4-chlor0- 30phenyl)salicylanilide (145-147). 33- 3 trifluorornethyl- 5- chloro-fl-(4-ch1orophenyl)sal1- 0 cylanilide (148-149). 34. 3 trifluoromethylAr,5-dichloro-3- t-chlorophenyl) 0 salicylanilide (166-169). 35.-3,%;),45-trichloro-3- (4-chlorophenyl) salicylanide (193- 0 364-methyls1fl1'ony1-2,5-dich1oro-3 (4-chlorophenyl) 0 salicylanilide(241-244).

At 0. 1 p.p.m.

Evaluation II The compounds of this invention of the aforedescribedgroups (a) and (b) which satisfy the formula 01 Cl 41-NH Y OH Z whereinB is hydrogen or, and preferably, chloro, and

wherein Y and Z are unlike members of the group hydrogen and nitro, areparticularly useful in destroying amphibious gastropods by applicationof same to their water environ in that they exhibit quick kills therein.For example, three snails (Planobarius corneas which is the species ofsnail host of the cyclocoelid Tracheoph ilus sisowi, the blood flukeBilharziella polonica and several other trematodes) of 6 to 8 weeks ofage are placed in a 200 x 32 mm. glass tube (two replicates each of saidthree snails) and thereto is added the compound to be evaluated in theform of an aqueous dispersion thereof having a concentration of 0.1 partper million, that is p.p.m. (This dispersion is prepared by dissolvingand/or dispersing sufiicient of the particular compound in 10 ml. ofacetone to make a one percent by weight solution or mixture thereof andthen adding suflicient water to give dispersions of the followingtabulated concentration.) The percent kill (that is the average of tworeplicates each of said three snails) at the exposure time of 6 hours atF. for each of the following itemized compounds at a 0.1 part permillion concentration was found to be as follows:

nc 0. 1 p.p.m.

Compound In the same Evaluation II at the end of 6 hour exposure at 80F. but employing the snail species (Australorbis glabratus, an innerhostof Schistosoma mansoni which is the cause of bilharziosis, 100 percentkills were obtained employing Compound Nos. 6, 22 and 8 above identifiedat a concentration of 0.1 part per million, respectively.

In combating the aquatic Gastropoda it is necessary to apply thegastropodicide to the waters or land areas adjacent thereto which formtheir habitats, and therefore to be practical the compounds of thisinvention must exhibit gastropodicidal activity at relatively highdilutions, for example 10- to 10" by Weight.

In combatting the amphibious Gastropoda the compounds of this inventioncan be employed per se or formulated into a dust and dispersed orscattered on the ground along banks of streams, rivers, irrigationcanals, or the edges of other bodies of water, e.g. the seashore, sothat the amphibious Gastropoda will come in contact with thegastropodicidal agent when it leaves the water and begins to travelacross ground areas.

Where the Gastropoda, whether aquatic or amphibious, sought to becombatted has a water habitat the compounds of this invention can beadded per se to the water, or in the form of a formulated dust cast onthe surface of the water, or sprayed on the water in the form of asolution thereof or a liquid emulsion formulation thereof.

Inert finely divided inert solid for the formulation of gastropodicidaldusts of this invention include fullers earth, diatomaceous earth,bentonite, talc, pyrophillite, soybean flour, wood flour, and walnutshell flour, which dusts preferably have a particle size of 5 microns orbelow and contain from 5 to percent by weight of a compound of thisinvention. Ordinarily such dusts will be applied at the rate of about 10to 50 pounds of gastropodicidal agent per acre of surface area. Thesedusts based on the total weight thereof can also contain from 1 to 15percent by weight of an anionic, or non-ionic surfactant or mixturesthereof to provide a wettable dust formulation. Liquid formulations canbe prepared by dissolving the compounds of this invention in a suitableorganic solvent such as acetone or butanone and sprayed as such or inadmixture with a non-ionic or anionic surfactant or mixtures thereof toform a liquid emulsion formulation for spray purposes.

In all of the forms described above the formulations can be providedready for use in combatting gastropods or they can be provided in aconcentrated form suitable for mixing with or dispersing in otherextending agents. As illustrative of a particularly useful concentrateis an intimate mixture of a compound of this invention with awater-soluble surfactant either non-ionic or anionic or mixtures thereofwhich lowers the surface tension of water in the weight proportions of0.1 to 15 parts of surfactant with suflicient of a compound of thisinvention to make 100 parts by weight. Such a concentrate isparticularly adapted to be made into a spray for destroying variousforms of gastropods by the addition of water thereto. As illustrative ofsuch a concentrate is an intimate mixture of 50 parts by weight of2',5-dichloro-5'-nitro-3- (4-chlorophenyDsaIicyI-anilide land 5.0 partsby weight of a watersoluble non-ionic surfactant such as polyoxyethylenederivative of sorbitan monolaurate.

Another useful concentrate adapted to be made into a spray forcombatting gastropods is a solution (preferably as concentrated aspossible) of a compound of this invention in an organic solventtherefor, for example acetone, cyclohexanone or acetophenone. The saidliquid concentrate preferably contains dissolved therein a minor amount(e.g. 0.5 to percent by weight of the weight of the new gastropodicidalagent) of a non-ionic, or anionic surfactant or mixtures thereof, whichsurfactant is also watersoluble. As illustrative of such a concentrateis a solution of 2',5-dichloro-4'-nitro-3-(4-chlorophenyl)salicylanilidein acetone which solution contains dissolved therein a water-solublealkylarylsulfonate anionic surfactant, e.g. sodiumdodecylbenzenesulfonate, or a water-soluble cationic surfactant of theC1242 fattyamine-ethyleneoxide condensate type.

Of the surfactants aforementioned in preparing the various emulsifiable,wettable or dispersible compositions or concentrates of this invention,the water-soluble anionic and non-ionic surfactants described in US.2,846,398 are preferred. Of the anionic surfactants, the particularlypreferred are the well-known water-soluble alkali metalalkylarylsulfonates as exemplified by sodium decylbenzenesulfonate andsodium dodecylbenzenesulfonate. Of the non-ionic surfactants theparticularly preferred are the water-soluble polyoxyethylene derivativesof alkylphenols (particularly isooctylphenol) and the water-solublepolyoxyethylene derivatives of the mono-higher fatty acid esters ofsorbitan containing to 30 moles of ethylene oxide per mole of sorbitanmono-ester of a higher fatty acid, e.g. oleic acid.

In all of the various dispersions described hereinbefore forgastropodicidal purposes, the active ingredient can be one or more ofthe compounds of this invention. The compounds of this invention canalso be advantageously employed in combination with other pesticides,including, for example, nematocides, bacterocides, and insecticides. Inthis manner it is possible to obtain mixtures which are effectiveagainst a wide variety of pests and other forms of noxious life.

The actual effective concentration of the compound of this invention forgastropodicidal purposes will depend upon the particular Gastropoda,weather conditions, and whether it is to be applied directly to thewater which forms the habitat for the Gastropoda or to land areas whichare crossed by amphibious Gastropoda either as the compound per se or inthe form of formulations thereof. Those skilled in this art can readilydetermine the proper concentration for any particular application byknowing the particular dilution factor, which is generally expressed asthe maximum aqueous dilution which will produce a 50% kill at a dilutionof one part by weight per 8000 parts structural formula l t NH@NO.

wherein A is halogen of atomic weight in the range of 35 to and B ishalogen of atomic weight in the range of 35 to 80.

2. A substituted 5-halo-3-phenylsalicylanilide of the structural formula7 l i mm wherein A is halogen of atomic weight in the range of 35 to 80;wherein B is selected from the group consisting of hydrogen and halogenof atomic weight in the range of 35 to 80.

3. 3' trifluoromethyl 4' nitro-5-chloro-3-(4-chlorophenyl)salicylanilide.

References Cited UNITED STATES PATENTS 3,231,465 l/1966 Early 260-5593,227,718 1/1966 Iohannis et al. 260-559 3,216,896 11/1965 Early et al260-559 3,113,067 12/1963 Strufe et al. 260--559 HENRY R. J ILES,Primary Examiner H. I. MOATZ, Assistant Examiner U.S. c1. X.R. 424 324

